Benzodiazepines and sedative hypnotics such as zolpidem ("z-drugs") are commonly prescribed for anxiety and sleep disorders. Epidemiologic evidence links their use to increased risk of venous thromboembolism. We investigated venous thromboembolism risk among concomitant users of individual benzodiazepines/z-drugs (examined separately) with other prescription medications to generate data-driven hypotheses about drug interactions resulting in clinically meaningful harm to inform future etiologic studies of specific drug combinations. We conducted a series of self-controlled case series studies within a 50% random sample of US Medicaid and Medicare data. Each cohort comprised person-time exposed to a benzodiazepine/z-drug, dichotomized into focal versus referent periods based on concomitant drug use versus non-use. We used conditional Poisson regression to estimate incidence rate ratios for hospital or emergency department presentation for venous thromboembolism. We generated ratios of incidence rate ratios, leveraging negative control analyses of eye drop-concomitant drug pairs, to minimize confounding by indication for the concomitant drug. We used semi-Bayes shrinkage to minimize false positives. Among 1590 self-controlled case series studies involving 8853 individuals with venous thromboembolism, 38 (2.4%) potential drug interaction signals were identified before calibration. After adjustment for multiple testing and negative control findings, five (0.3%) signals remained, involving gabapentin combined with eszopiclone, lorazepam, clonazepam, or alprazolam, and apixaban combined with diazepam (ratio of incidence rate ratio range: 1.92-3.57). Four (80%) involved concurrent use of gabapentin, a medication largely used to treat neuropathic pain. Most benzodiazepine/z-drug combinations conferred no increased venous thromboembolism risk. However, concurrent use of a benzodiazepine/z-drug with gabapentin may increase the relative rate of venous thromboembolism up to 3.5-fold. As this work was hypothesis generating, a future etiologic study should confirm this potential drug interaction.
Current evidence for individuals experiencing Type 2 Diabetes (T2D), who refuse insulin treatment and are given five non-insulin antidiabetic drug combinations, is scarce. We conducted a retrospective observational study to investigate the prevalence of quintuple non-insulin drug regimens during a 12-month period, in patients with suboptimally controlled T2D who refuse insulin therapy. 1463 individuals with T2D were assessed during the course of the investigation. Forty patients (2.7%) satisfied the eligibility criteria and were included. The mean therapeutic period was 35.5 ± 29.2 months, and the mean A1C was 7.5± 1.0%. The majority of patients received pioglitazone as the fifth choice to background quadruple regimens (70%). The mean decrease in A1C levels was 0.82 ± 0.99% compared to baseline indices without notable side effects and safety concerns (p < 0.001). Fear of starting insulin was the major reason for rejecting insulin therapy. Despite the limitations inherent to its retrospective design, this study shows that five non-insulin drug combinations can be considered a possible therapeutic option for this difficultto-treat group of patients, at least until they are convinced to start and maintain insulin therapy. The prevalence of individuals with T2D treated with quintuple non-insulin drug regimens was 2.7% without any notable side effects or safety concerns. In patients who refuse insulin therapy, these combinations can be taken into consideration according to the characteristics of every individual and carefully evaluated for their safety and effectiveness.
We evaluated in vitro activity of thymol in combination with β-lactams, gentamicin, or colistin against Carbapenem-Resistant Acinetobacter baumannii (CRAb) and KPC-producing Klebsiella pneumoniae (KPC-Kp) clinical isolates displaying different susceptibility profiles. Thymol, when combined with β-lactams, did not exert synergistic interactions, whereas in association with colistin it showed additive or synergistic activity against 85.7% (6/7) and 14.3% (1/7) of MDR-GNB clinical isolates, respectively. These results showed that thymol in association with colistin may be considered a potential strategy that warrants further investigation as a potential antimicrobial-adjuvant strategy for patients colonized by MDR-GNB clinical isolates, also hypothesizing the ability to reduce the spread of emerging resistance traits.
The HLA-B*15:02 allele is related to a high risk of severe cutaneous adverse drug reactions (SCARs) in patients taking certain antiepileptic drugs. However, its prevalence in the Asian population and the number of drugs linked to SCARs due to the carriage of this variant are relatively underexplored. This study sought to address these knowledge gaps. The prevalence of the HLA-B*15:02 allele in Asian populations was estimated by using the data from the Allele Frequency Net Database. Weighted means, standard deviations, and 95% Confidence Interval (CI) were estimated for the study populations, and the chi-square test was used to assess the statistical significance of variability in allele frequencies across populations. Drugs associated with SCARs due to HLA-B*15:02 were identified from the clinical guidelines of the international pharmacogenomics (PGx) working groups. HLA-B*15:02 was most prevalent in South-East Asia (5.6% ± 3.1), followed by South Asia (2.1% ± 1.5), North-East Asia (0.6% ± 0.9), and West Asia (0.01% ± 0.05). This distribution was statistically significant (χ2 = 9712.5, df = 3, p < 0.001; χ 2 test). Country-wise, prevalence was the highest in the Philippines (22%; 95% CI, 11.53-35.96%), followed by Vietnam (13.5%; 95% CI, 8.77-19.61%), Indonesia (11.9% ± 1.5), Malaysia (10% ± 4.3), Hong Kong (9.3% ± 0.2), Thailand (8.4% ± 0.1), Singapore (8.1% ± 3.7), China (5.4% ± 5.4), Taiwan (4.4% ± 0.7), Sri Lanka (2.5%, single study), India (2.1% ± 1.5) and South Korea (1.5% ± 0.9). PharmGKB clinical annotations identified four drugs (carbamazepine, oxcarbazepine, lamotrigine, phenytoin) with strong evidence (Level 1 A) for HLA-B*15:02-related SCARs, though the majority of the evidence for lamotrigine came from the Han Chinese Population. International PGx working groups require or recommend preemptive HLA-B*15:02 genotyping for at least three drugs, i.e., carbamazepine, oxcarbazepine, and phenytoin. Considering the high prevalence of the HLA-B*15:02 in the Southeast and South Asians, and its association with drug-induced SCARs, pre-emptive HLA-B*15:02 testing may reduce SCARs substantially in this region.
Antimicrobial resistance (AMR) by Pseudomonas aeruginosa, within urinary tract and nosocomial infections, involves biofilm formation and quorum sensing (QS) constituting a major clinical challenge. The chemical composition of Pelargonium graveolens essential oil (EO) was determined by gas chromatography-mass spectrometry (GC-MS). Antibacterial activity of the EO and its major constituents, citronellol and geraniol, was evaluated against clinical and reference P. aeruginosa strains using disk diffusion and broth microdilution assays. Antibiofilm activity was assessed at concentrations ranging from 2×MIC to sub-MIC levels. Interference with quorum-sensing-associated phenotypes was investigated using Chromobacterium violaceum CV12472 and CV026 biosensor strains. Swarming and swimming motility assays were performed. Molecular docking and ADMET analyses were conducted to explore potential target interactions and pharmacokinetic properties. Citronellol (34.29%) and geraniol (18.62%) were the predominant constituents of the EO. Antibacterial activity yielded inhibition zones of 10-14 mm and MIC values ranging from 1% to 0.031% (v/v), with geraniol showing the lowest MIC (0.031%). The EO, citronellol, and geraniol inhibited biofilm formation, reaching 87.28% inhibition at 2×MIC while retaining activity at sub-MIC concentrations. All treatments reduced violacein production in C. violaceum biosensors and inhibited bacterial motility, with maximum reductions of 82.6% (swarming) and 74.3% (swimming). Geraniol generally exhibited the strongest activity. Docking analysis revealed binding affinities of - 6.08 and - 5.83 kcal/mol for citronellol and geraniol, respectively. P. graveolens EO, citronellol, and geraniol exhibited promising anti-virulence properties against multidrug-resistant uropathogenic P. aeruginosa, supporting their potential as complementary agents for controlling biofilm- and motility-associated infections.
The combination of amisulpride and metformin is common in schizophrenia, but their potential drug-drug interaction has been largely overlooked, despite both drugs being prototypical substrates for renal elimination and potentially subject to transport by OCT2 and MATE1. In this study, we employed population pharmacokinetic modeling to quantify the impact of renal function and metformin on amisulpride pharmacokinetics, and complemented it with molecular docking to predict binding modes on key renal transporters, thereby exploring potential transporters mediating the interaction. We identified CLcr, assessed by the Cockcroft-Gault formula, as the dominant covariate. A 10% decrease in CLcr was associated with a 3.8% decrease in CL/F, while metformin significantly reduced clearance by 23.2%, leading to an at least 41% increase in amisulpride steady‑state trough concentration. Molecular docking generated a structural hypothesis that amisulpride and metformin may share overlapping binding sites on OCT2 and MATE1. This study provides the first clinical indication of a potential drug-drug interaction between amisulpride and metformin. We provide model‑informed dosing references stratified by CLcr, along with recommendations for dose reduction and heightened vigilance for interaction-related adverse effects in patients receiving combination therapy. Molecular docking offers a structural hypothesis regarding binding at OCT2 and MATE1 to support further mechanistic investigation.
To systematically evaluate safety signals of selective serotonin reuptake inhibitors (SSRIs) associated with drug-induced liver injury (DILI) using the FAERS database, and to explore potential toxicological mechanisms through drug-gene interaction network analysis. Adverse event data for six SSRIs (2013-2023) were extracted from FAERS. Descriptive analysis and disproportionality signal detection (ROR, BCPNN) were performed. Time to DILI onset and factors influencing mortality were analyzed. Network pharmacology explored drug-gene interactions. Due to the absence of individual-level clinical data in FAERS, we could not apply the updated RUCAM, the gold standard for DILI causality assessment. DILI reports were most frequent in patients aged 18-64 years and in females. Sertraline had the highest number of reports; fluvoxamine the fewest. Common signals across SSRIs included hepatocellular injury and necrosis. Fluoxetine showed unique signals for hepatic steatosis, paroxetine for chronic active hepatitis, and sertraline for severe liver failure (e.g., primary biliary cholangitis, hemorrhagic hepatic cyst). Median time to onset was within the first month of treatment. Age 18-44 years (OR = 3.03, 95% CI: 1.12-8.18) and low body weight ≤60 kg (OR = 0.45, 95% CI: 0.18-1.14) were significant predictors of mortality. Network analysis suggested shared mechanisms (e.g., CYP450 dysfunction, apoptosis dysregulation) and drug-specific pathways (e.g., PI3K-Akt for sertraline, IL-17 signaling for fluoxetine/fluvoxamine). DILI safety signals for SSRIs are most frequent within the first month of treatment, particularly in female patients. Considerable variability in hepatotoxicity profiles among SSRIs supports drug-specific monitoring. These hypothesis-generating findings provide a basis for personalized risk assessment and require confirmation in prospective studies.
Pulmonary arterial hypertension (PAH) is a progressive and life-threatening condition characterized by elevated pulmonary vascular resistance eventually causing right ventricular failure and premature death. Despite advances in targeted therapies, morbidity and mortality levels remain high, highlighting the need for additional treatment strategies that address the disease's multifactorial pathophysiology. Attention has recently centred on two pharmacological groups with proven roles in other cardiovascular settings: sodium-glucose cotransporter 2 inhibitors (SGLT2i) and mineralocorticoid receptor antagonists (MRAs). SGLT2 inhibitors have demonstrated robust clinical benefits in heart failure (HF), type 2 diabetes mellitus (T2DM), and chronic kidney disease (CKD), extending survival and reducing hospitalizations. Although their primary actions involve renal glucose and sodium handling, accumulating evidence suggests they may also exert favourable effects on the pulmonary vasculature, endothelial function, and right ventricular performance. In parallel, elevated aldosterone levels have been implicated in vascular remodelling, inflammation, and fibrosis in PAH, suggesting a potential therapeutic role for MRAs. However, the strength and clinical significance of these associations remain under investigation. The aim of this review is to synthesize and critically appraise the current evidence regarding the potential role of SGLT2 inhibitors and MRAs in the treatment of pulmonary arterial hypertension, exploring their mechanistic rationale, preclinical findings, and available clinical data to determine whether these agents may offer additional therapeutic benefit in PAH management.
Lithium, the gold-standard treatment for bipolar disorder, exhibits highly heterogeneous clinical responses and no validated biological predictors of responsiveness are currently available. Emerging evidence suggests that the gut microbiota influences mood disorders and psychotropic drug response, raising the hypothesis that specific microbial signatures may modulate lithium responsiveness. In this study, we characterized taxonomic and functional gut microbiota profiles in 77 patients with bipolar disorder, of whom 40 were receiving lithium (20 responders, 20 non-responders) and 37 were treated with valproate as the main mood stabilizer (valproate, n = 31; lamotrigine, n = 6), with the aim of identifying potential microbial markers of clinical response. Microbiota composition was assessed through 16S rRNA sequencing targeting the V3-V4 region. Differential abundance was evaluated using Analysis of Composition of Microbiomes with Bias Correction (ANCOM-BC2), and the functional potential was inferred using the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 (PICRUSt2). Our finding showed that lithium treatment was associated with a selective gut microbiota reorganization, including reduced Actinobacteria (Actinomycetota) phylum, notably Coriobacteriia class, and enrichment in Firmicutes (Bacillota) taxa, including Selenomonadales, Megamonas and Clostridia taxa, alongside reductions in primary fermentative and biosynthetic pathways. This shift, characterized by a reduction of primary fermenters and enrichment of secondary fermenters and SCFA-producing taxa, suggests a more efficient fermentative ecosystem in lithium-treated patients. Responders showed enrichment in methanogenic taxa (Methanobrevibacter) and Clostridiales vadinBB60 group when compared with patients treated with other mood stabilizers; however, these differences were not observed in the direct comparison between lithium responders and non-responders. While causal relationships cannot be inferred, these findings indicate treatment-associated microbial patterns and support further investigation into microbiota-directed adjunctive therapies.
Charcot-Marie-Tooth disease type 1 (CMT1) is a rare, genetically diverse condition and represents the most prevalent form of inherited peripheral neuropathy, characterized by Schwann cell dysfunction resulting in progressive demyelination and muscle wasting. CLZ-2002, an allogeneic Schwann cell-like product derived from human tonsillar mesenchymal stem cells, has been developed as a regenerative therapy and investigated in CMT1 patients. A Phase 1, open-label, dose-escalation clinical trial was performed in nine patients with genetically diagnosed CMT1 (five with CMT1A, four with CMT1B). Participants were allocated to three dosing cohorts: 6 million (G1), 12 million (G2), or 24 million cells (G3). CLZ-2002 was delivered as a single intramuscular injection into the lower limbs. The primary objective was to assess safety and tolerability. Exploratory endpoints included Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2), Overall Neuropathy Limitation Score-leg (ONLS-leg), Functional Disability Score (FDS), electrophysiology, MRI, and circulating biomarkers. No drug-related adverse reactions, serious adverse events, or dose-limiting toxicities occurred. Four participants experienced a total of five grade 1-2 treatment-emergent adverse events. By Week 24, improvements relative to baseline were noted in CMTNSv2 and ONLS-leg. Biomarker levels of NCAM1 and GDF15 declined at Week 4 but returned toward baseline by Week 24, reflecting the observed clinical trends. A single intramuscular dose of CLZ-2002 of up to 24 million cells was safe and well-tolerated in CMT1 patients. Exploratory efficacy assessments suggested possible clinical benefit, warranting continued investigation of CLZ-2002 in larger, controlled study populations.
Huntington disease (HD) is a debilitating, genetic disorder with a prevalence of 2.7 per 100,000 people. It is neurodegenerative, leading to cognitive, behavioral, and motor symptoms from neuronal loss within the striatum of the basal ganglia and cortex. Currently, the treatments involve symptomatic management, instead of treating the pathophysiology of the disease. Grape seed extract (GSE) is a complex mixture of polyphenols, proteins, and lipids with antioxidant and anti-inflammatory properties. This literature review examines the possibility of using GSE as a potential adjunctive therapy for HD. Preclinical studies have shown a neuroprotective effect through biologically plausible mechanisms. Clinical research has shown that GSE works on redox and inflammatory pathways related to the pathogenesis of HD. Although there are not many clinical trials on GSE in HD patients directly, the overlap of mechanisms behind both GSE and HD and the favorable side effect profile make GSE a potential adjunctive therapy. Targeted clinical investigation is warranted to determine the full therapeutic potential of GSE.
Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV), members of the family Pneumoviridae, represent a foremost global cause of acute lower respiratory tract infection in infants, young children, the elderly, and immunocompromised individuals. Despite the recent approval of preventive vaccines and monoclonal antibody prophylactics targeting the viral fusion protein, no widely adopted, RSV-specific direct-acting antiviral is currently approved for routine post-infection treatment. The large (L) protein of the viral RNA polymerase complex, which catalyzes genome replication and mRNA transcription in concert with its obligate cofactor, the phosphoprotein (P), constitutes an ideal drug target owing to its essential and multifunctional enzymatic activities and its absence from host cells. Over the past decade, Cryo-electron microscopy (Cryo-EM) has yielded a series of landmark structures of Pneumoviridae L-P complexes, including apo forms of RSV (at 3.2-3.67 Å) and hMPV (at 3.7 Å) polymerases, among the first promoter-bound non-segmented negative-sense (nsNSV) RNA virus polymerase structures (at 3.40-3.41 Å), and inhibitor-bound complexes that illuminate the molecular basis of non-nucleoside inhibitor (NNI) action at sub-nanomolar potency. This review synthesizes the structural biology of Pneumoviridae RNA polymerases from a chronological and mechanistic perspective, compares RSV and hMPV L protein active sites at near-atomic resolution, and critically evaluates how structural insights are being translated into next-generation antiviral drug candidates, including nucleoside analog inhibitors, allosteric non-nucleoside inhibitors, and emerging candidates at various stages of preclinical and clinical investigation.
Cervical dystonia (CD) is a focal dystonia typically treated with botulinum toxin type A (BoNT-A), but objective biomarkers of disease state and treatment response are limited. In a prospective controlled observational study with within-subject phase comparison, we evaluated clinical, neurophysiological, and biochemical markers at two time points (waning and peak response phases) within the BoNT-A injection interval in 30 CD individuals (with caput, collis and mixed patterns) and 25 healthy controls. We measured clinical status (TWSTRS and VAS pain), neurophysiology (F-wave minimal latency (F-min) and cutaneous silent period (CSP) indices) and plasma biochemical markers (neurofilament light chain (NfL) and zonulin). Compared with controls, CD patients showed lower NfL levels, higher zonulin, shorter CSP end duration and shorter CSP-derived central conduction time (CSP-CCT); nerve conduction velocity and CSP onset were similar. From waning to peak, TWSTRS (all subscales) and VAS improved, zonulin decreased, NfL increased, CSP end duration and CSP-CCT increased, and Fmin slightly prolonged. Changes in CSP measures correlated with pain (VAS and TWSTRS pain), while zonulin changes showed no significant correlations and NfL changes correlated weakly/negatively with CSP end time. Phase-dependent changes in biochemical and neurophysiological markers were observed alongside clinical measures across the BoNT-A treatment cycle in CD, suggesting potential associations between peripheral biochemical markers, central inhibitory measures, and treatment phase. These findings may warrant further investigation of multimodal biomarker approaches in CD.
Dolutegravir underpins modern first- and second-line HIV treatment regimens; however, interindividual variability in its disposition and tolerability presents challenges for optimal use. This scoping review mapped current evidence on the pharmacogenomics of dolutegravir, focusing on pharmacokinetics and pharmacodynamics, and methodological limitations of existing studies. Reduced-function UGT1A1 alleles (*6, *28, *37) emerged as the most consistent determinants of increased dolutegravir exposure across African, European and Asian populations, reinforcing UGT1A1 as the predominant genetic pathway for dolutegravir clearance. Transporter polymorphisms, particularly in ABCG2, showed variable associations with dolutegravir concentrations, with differing results in children compared with adults. Genome-wide association studies in African populations have identified novel candidate loci (e.g., CAMKMT and MIR99AHG) requiring replication. Evidence linking genetic variation to clinical outcomes remains weak: Associations with neuropsychiatric adverse events (notably in UGT1A1 and SLC22A2), weight gain (ABCG2, MC4R and TMEM163) and viral suppression were inconsistent and underpowered. Suggestive gene-gene and gene-drug interactions merit further investigation. The current evidence base is constrained by small sample sizes, heterogeneous study designs, overlapping datasets, non-adjustment for multiple testing, limited ancestral diversity and inconsistent phenotyping. Overall, UGT1A1 variation is the only reproducible pharmacogenomic signal of clinical relevance; however, its effect size does not currently justify routine genotype-guided dosing. In the future, priority should be given to well-powered, multi-ancestry, harmonised studies with functional validation to clarify the role of pharmacogenomics in tailoring dolutegravir-based therapy.
Natural killer cell large granular lymphocytic leukemia (NK-LGLL) is a rare and heterogenous lymphoproliferative disorder. This study retrospectively evaluated 35 consecutive Chinese patients (median age 58 years) to evaluate their unique clinical-biological profiles and treatment responses. Our Chinese population exhibited a distinct comorbidity spectrum, characterized by a lower prevalence of concurrent arthritis (2.9%) and secondary malignancies, compared with Western cohorts. At diagnosis, 31.4% of the cohort had neutropenia, 42.9% had anemia, and 31.4% had thrombocytopenia. The median large granular lymphocyte count was 3.9 × 109/L (range 0.11-114.8 × 109/L; IQR 1.9 × 109/L, 5.9 × 109/L). Immunophenotyping consistently identified as a CD3- CD56+ clone. Notably, genomic profiling via NGS revealed a STAT3 mutation rate of 14.3%. Regarding therapeutic efficacy, frontline immunosuppressive therapy with cyclophosphamide or cyclosporine was associated with favorable clinical responses (best overall response, complete remission rate 66.7% for both). Additionally, sirolimus emerged as a potentially highly effective salvage option, yielding an overall response rate of 85.7% (95%CI 42.1-99.6%) and complete remission rate of 57.1%. With an estimated 3-year overall survival rate of 85.6% (95%CI 73.3%, 99.8%), our findings suggest a generally indolent clinical course of NK-LGLL in this Chinese cohort and highlight the potential of mTOR inhibition in refractory cases, warranting further prospective investigation.
The latest drug-eluting stents (DESs) are the gold standard for patient treatment during percutaneous coronary intervention (PCI). The latest advancements in DES innovation have resulted in the development of new stent technologies with reduced thickness in the struts. The new DES design, ultrathin-strut DESs, features struts measuring less than 70 μm in thickness. The evidence for these devices is derived from observational studies, extensive meta-analyses, and randomized trials with long-term outcomes. The investigation is focused on determining the comparative performance of ultrathin-strut DESs and conventional new-generation DESs across various clinical settings and patient lesion profiles. The objective of the seminar is to examine recent advancements in the use of very thin DESs and the potential of computational modeling in coronary arteries during PCI. An analysis of the mechanical performance of ultrathin DESs has been conducted in terms of radial expansion and stresses within the stent-vessel system. Residual stresses generated by the crimping process will also be considered.
Anorexia nervosa (AN) carries the highest mortality of any psychiatric disorder, yet no pharmacological agent has received regulatory approval for its treatment in adults. Multimodal neuroimaging has now revealed a coherent neurobiological architecture: functional MRI documents blunted ventral striatal and amygdalar responses to food, alongside excessive prefrontal-cingulate engagement; PET corroborates trait-level reductions in 5-HT2A binding, elevations in 5-HT1A binding across cingulate, frontal, parietal, temporal, and dorsal raphe regions, and compensatory upregulation of D2/D3 receptors in the anteroventral striatum; SPECT identifies persistent temporal and cingulate hypoperfusion; and EEG reveals attenuated P300 amplitudes, delayed N2 latencies, and parieto-occipital theta hyperarousal. We propose that cariprazine-a dopamine D3-preferring D3/D2 receptor partial agonist with 5-HT1A partial agonism and 5-HT2A/2B antagonism-confers a uniquely matched pharmacological toolkit for this disorder. Cariprazine's D3 partial agonism is predicted to restore mesolimbic dopamine signaling, thereby reinstating incentive salience to food cues; its 5-HT1A stabilizer property attenuates the trait-amplified corticolimbic inhibitory tone underlying harm avoidance and anxiety; its prefrontal glutamate-modulating action attenuates excessive cognitive control over eating, and chronic administration confers substrate-dependent set-point recalibration of the upregulated mesolimbic D3 receptor pool. Furthermore, cariprazine's favorable metabolic profile (number needed to harm for clinically significant weight gain of 34 versus 6 for olanzapine) renders its safety burden meaningfully lower than that of currently used agents. In summary, the receptor pharmacology of cariprazine maps with notable specificity onto the neuroimaging-defined substrate of AN, providing a mechanistically grounded rationale for prospective clinical investigation of cariprazine as a candidate pharmacotherapy for this otherwise intractable disorder.
Pseudomonas aeruginosa is an opportunistic pathogen causing healthcare-associated infections. Colistin is a last-resort antibiotic for multidrug-resistant Gram-negative bacteria. Resistance arises through mutations in two-component systems (TCS) regulating the arn operon. Data on colistin resistance in P. aeruginosa from Pakistan remain limited. A total of 3189 clinical samples (urine, blood, sputum, pus, wound swabs) were cultured. P. aeruginosa was identified by Gram staining, biochemical tests (catalase, oxidase, API 20E), and oprL gene amplification. Antibiotic susceptibility was determined by disk diffusion and MIC strips. Resistance genes (PhoP, PhoQ, PmrA, PmrB, mcr-1, oprD) were detected by PCR and Sanger sequencing. Wild-type protein structures were retrieved from PDB; mutant structures were predicted using AlphaFold3. ANP (phosphoaminophosphonic acid-adenylate ester) was docked using MOE 2019.0102. Of 3189 samples, 384 (12.0%) yielded P. aeruginosa. Wound/pus (38.0%) and surgical wards (30.0%) were the predominant sources. Colistin and polymyxin B showed 99.0% susceptibility (MIC50/MIC90 = 1 µg/mL). High resistance was observed for Piperacillin-Tazobactam (96.4%), Aztreonam (70.6%), and Gentamicin (64.2%). oprD was the most prevalent gene (87.5%), followed by PmrB (54.0%), PhoQ (44.0%), PhoP (36.0%), PmrA (18.0%), and mcr-1 (8.0%). Docking revealed the strongest binding in wild-type PhoQ (1ID0; -12.0 kcal/mol, LYS392), wild-type PmrB (2JSO; -9.8 kcal/mol, ASP37), and wild-type PhoP (2PKX; -9.1 kcal/mol, LYS87/ARG111). Mutant proteins showed reduced binding affinities and dispersed interaction networks. Mutant PhoP formed 16 contacts (strongest -4.3 kcal/mol) versus wild-type PhoP with 13 contacts (-9.1 kcal/mol). Colistin remains highly effective against P. aeruginosa in this setting (99.0% susceptibility). The presence of mcr-1 (8.0%) and high oprD prevalence (87.5%) require continued surveillance. Mutations in TCS proteins reduce ANP binding affinity and alter interaction specificity, suggesting that ATP-competitive inhibitors targeting these kinases merit further investigation and experimental validation.
Testosterone therapy may benefit postmenopausal women beyond treating low sexual desire and shows cardiovascular safety with potential protective effects. While improvement in sexual desire remains the only guideline-supported indication, expanding research has prompted investigation into testosterone's broader physiologic effects. Evidence supports cardiovascular safety with potential protective vascular effects as well as improvements in sexual function, genitourinary health, lubrication, and tissue integrity. Long-term safety data remain limited, though serious adverse events appear uncommon when testosterone levels are maintained within normal female ranges. These emerging applications should be viewed as hypothesis-generating and do not yet support guideline-level changes to clinical practice.
Prescription errors remain a significant challenge to medication safety in hospital settings. Forced Interception (FI) systems, which automatically flag and block potentially problematic prescriptions, serve as critical safeguards against adverse drug events. However, the specific characteristics and underlying causes of intercepted prescriptions, particularly in Chinese hospital contexts, require further investigation to inform targeted quality improvement strategies. This study aimed to analyze the characteristics and interception reasons of FI prescriptions in a hospital setting, with the goal of identifying patterns that could guide system upgrades, clinical training, and policy interventions. This study conducted a retrospective analysis of FI prescriptions intercepted by the hospital's electronic prescribing system. Prescriptions were analyzed for interception reasons, drug categories, specific medications, and prescribing department patterns. Data were collected and categorized to identify the most frequent issues and drug types involved in forced interceptions. A total of FI prescriptions were analyzed. The most common interception reasons were "Treatment duration exceeded" (54.89%) and "Exceeding Dosage" (28.11%), together accounting for the majority of interceptions. Traditional Chinese medicine and central nervous system drugs were the most frequently intercepted drug categories. The top three intercepted medications were Duloxetine Hydrochloride Enteric Capsules (3.63%), Atorvastatin Calcium Tablets (3.11%), and Tandospirone Citrate Capsules (2.81%). Departmental analysis revealed distinct prescribing patterns: the cardiology department showed high interceptions for hyperlipidemia-related drugs, while the mental health department had numerous interceptions for long-term antidepressant and anxiolytic prescriptions. The study suggests that targeted interventions, including upgrading electronic prescribing systems, department-specific training, and forming special review panels, are necessary to reduce prescription errors and improve medication safety. Future work should focus on multicenter studies and, as a longer-term direction, explore the potential of artificial intelligence for dynamic risk prediction to enhance the continuous optimization of medical quality.